Identification of sequence variants influencing immunoglobulin levels

Stefan Jonsson; Gardar Sveinbjornsson; Aitzkoa Lopez De Lapuente Portilla; Bhairavi Swaminathan; Rosina Plomp; Gillian Dekkers; Ram Ajore; Mina Ali; Arthur E.H. Bentlage; Evelina Elmér; Gudmundur I. Eyjolfsson; Sigurjon A. Gudjonsson; Urban Gullberg; Arnaldur Gylfason; Bjarni V. Halldorsson; Markus Hansson; Hilma Holm; Åsa Johansson; Ellinor Johnsson; Aslaug Jonasdottir; Bjorn R. Ludviksson; Asmundur Oddsson; Isleifur Olafsson; Sigurgeir Olafsson; Olof Sigurdardottir; Asgeir Sigurdsson; Lilja Stefansdottir; Gisli Masson; Patrick Sulem; Manfred Wuhrer; Anna Karin Wihlborg; Gudmar Thorleifsson; Daniel F. Gudbjartsson; Unnur Thorsteinsdottir; Gestur Vidarsson; Ingileif Jonsdottir; Björn Nilsson; Kari Stefansson

doi:10.1038/ng.3897

Identification of sequence variants influencing immunoglobulin levels

Stefan Jonsson, Gardar Sveinbjornsson, Aitzkoa Lopez De Lapuente Portilla, Bhairavi Swaminathan, Rosina Plomp, Gillian Dekkers, Ram Ajore, Mina Ali, Arthur E.H. Bentlage, Evelina Elmér, Gudmundur I. Eyjolfsson, Sigurjon A. Gudjonsson, Urban Gullberg, Arnaldur Gylfason, Bjarni V. Halldorsson, Markus Hansson, Hilma Holm, Åsa Johansson, Ellinor Johnsson, Aslaug JonasdottirBjorn R. Ludviksson, Asmundur Oddsson, Isleifur Olafsson, Sigurgeir Olafsson, Olof Sigurdardottir, Asgeir Sigurdsson, Lilja Stefansdottir, Gisli Masson, Patrick Sulem, Manfred Wuhrer, Anna Karin Wihlborg, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Gestur Vidarsson, Ingileif Jonsdottir^*, Björn Nilsson, Kari Stefansson

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

36 Citations (Scopus)

Abstract

Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10 -55, β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10 -8, β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.

Original language	English
Pages (from-to)	1182-1191
Number of pages	10
Journal	Nature Genetics
Volume	49
Issue number	8
DOIs	https://doi.org/10.1038/ng.3897
Publication status	Published - 1 Aug 2017

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Jonsson, S., Sveinbjornsson, G., De Lapuente Portilla, A. L., Swaminathan, B., Plomp, R., Dekkers, G., Ajore, R., Ali, M., Bentlage, A. E. H., Elmér, E., Eyjolfsson, G. I., Gudjonsson, S. A., Gullberg, U., Gylfason, A., Halldorsson, B. V., Hansson, M., Holm, H., Johansson, Å., Johnsson, E., ... Stefansson, K. (2017). Identification of sequence variants influencing immunoglobulin levels. Nature Genetics, 49(8), 1182-1191. https://doi.org/10.1038/ng.3897

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abstract = "Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10 -55, β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10 -8, β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.",

author = "Stefan Jonsson and Gardar Sveinbjornsson and {De Lapuente Portilla}, {Aitzkoa Lopez} and Bhairavi Swaminathan and Rosina Plomp and Gillian Dekkers and Ram Ajore and Mina Ali and Bentlage, {Arthur E.H.} and Evelina Elm{\'e}r and Eyjolfsson, {Gudmundur I.} and Gudjonsson, {Sigurjon A.} and Urban Gullberg and Arnaldur Gylfason and Halldorsson, {Bjarni V.} and Markus Hansson and Hilma Holm and {\AA}sa Johansson and Ellinor Johnsson and Aslaug Jonasdottir and Ludviksson, {Bjorn R.} and Asmundur Oddsson and Isleifur Olafsson and Sigurgeir Olafsson and Olof Sigurdardottir and Asgeir Sigurdsson and Lilja Stefansdottir and Gisli Masson and Patrick Sulem and Manfred Wuhrer and Wihlborg, {Anna Karin} and Gudmar Thorleifsson and Gudbjartsson, {Daniel F.} and Unnur Thorsteinsdottir and Gestur Vidarsson and Ingileif Jonsdottir and Bj{\"o}rn Nilsson and Kari Stefansson",

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Jonsson, S, Sveinbjornsson, G, De Lapuente Portilla, AL, Swaminathan, B, Plomp, R, Dekkers, G, Ajore, R, Ali, M, Bentlage, AEH, Elmér, E, Eyjolfsson, GI, Gudjonsson, SA, Gullberg, U, Gylfason, A, Halldorsson, BV, Hansson, M, Holm, H, Johansson, Å, Johnsson, E, Jonasdottir, A, Ludviksson, BR, Oddsson, A, Olafsson, I, Olafsson, S, Sigurdardottir, O, Sigurdsson, A, Stefansdottir, L, Masson, G, Sulem, P, Wuhrer, M, Wihlborg, AK, Thorleifsson, G, Gudbjartsson, DF, Thorsteinsdottir, U, Vidarsson, G, Jonsdottir, I, Nilsson, B & Stefansson, K 2017, 'Identification of sequence variants influencing immunoglobulin levels', Nature Genetics, vol. 49, no. 8, pp. 1182-1191. https://doi.org/10.1038/ng.3897

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AU - Dekkers, Gillian

AU - Ajore, Ram

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AU - Gudjonsson, Sigurjon A.

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AU - Halldorsson, Bjarni V.

AU - Hansson, Markus

AU - Holm, Hilma

AU - Johansson, Åsa

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AU - Jonasdottir, Aslaug

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AU - Thorleifsson, Gudmar

AU - Gudbjartsson, Daniel F.

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AU - Jonsdottir, Ingileif

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AB - Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10 -55, β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10 -8, β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.

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Identification of sequence variants influencing immunoglobulin levels

Abstract

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